T699P
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialThreonine → Proline at position 699 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.914, DynaMut2 ΔΔG -0.14 kcal/mol (mild destabilising). Proline-introduction adjacent to W700 (Cat 2 outlier region).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | F825 | F825 | Preserved |
| Polar contact | F825 | — | Lost |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
Clinical Evidence
Observed at very low frequency in gnomAD.
Structural Context
Position 699 sits in wolframin's C-terminal lumenal domain, immediately preceding W700 (the position of W700S — Cat 2 outlier — and W700C in the Atlas). The AlphaFold model places T699 within 5 Å of TRP700 (2.4 Å), VAL698 (2.5 Å), PHE825 (3.4 Å — W700's aromatic-stacking partner), and SER826 (4.3 Å).
The wild-type threonine at 699 sits in immediate contact with W700 and the F825 aromatic neighbor. The hydroxyl group H-bonds locally and stabilizes the geometry that supports W700's aromatic packing with F825.
Replacing T699 with proline introduces a backbone kink immediately upstream of W700, perturbing the precise W700-F825 π-stacking geometry the Atlas's W700C card identifies as the key functional contact. The |ΔΔG| of 0.14 is small (fold absorbs), but the functional consequence — disrupted W700 stacking — is the same severe pathogenic mechanism that pulls W700C into pathogenic territory.
Druggability Assessment
Mechanism is backbone kink upstream of W700 that perturbs W700-F825 π-stacking geometry. Therapeutic strategy: same target as W700C/W700S — the W700-F825 aromatic stacking microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the T699P PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.